Acute hepatitis C virus (HCV) infections in North Carolina increased 228% and heroin-related deaths increased 884% between 2010 and 2015. The NC Department of Health and Human Services (DHHS) conducted a vulnerability assessment and identified eight rural western counties with high rates of acute HCV, chronic HCV, and opioid overdose fatalities. RTI International, the University of NC at Chapel Hill, NC DHHS, local health departments (LHD), and the NC Harm Reduction Coalition are partnering in response to the RFA ?HIV, HCV and Related Comorbidities in Rural Communities Affected by Opioid Injection Drug Epidemics in the United States: Building Systems for Prevention, Treatment and Control.? Our team is ideally positioned in NC to develop, implement, and evaluate sustainable strategies for combatting opioid-associated adverse outcomes in rural people who inject drugs (PWID). The specific aims of the project by UG3/UH3 phase are as follows: UG3?1. Conduct 80 (10 per county) semistructured interviews with PWID; begin recruiting PWID using respondent-driven sampling (n=400) and LHDs and syringe service programs (SSPs; n=200); and use baseline self-reported data and HCV and HIV testing results to describe the care cascade for HCV, HIV, and substance use disorders. UG3?2. Survey (mail, electronic and telephone; n=150) LHD personnel, primary care, emergency/urgent care, and behavioral health care professionals (HCPs) in all eight counties to assess practice characteristics; awareness of and adherence to substance use, HCV, and HIV screening guidelines; and attitudes regarding implementation of SSPs, HCV care, and HIV care across practice settings. Conduct meetings with a subset of stakeholders. UG3?3. Informed by participants, identify health centers serving PWID in Jackson and Haywood counties, randomize implementation order, and train providers on prevention and treatment of HCV, HIV, and opioid overdoses. Assessing knowledge and practice patterns at baseline and 18 months after training (incentivized with continuing education units) will allow us to gauge training impact. After successful completion of UG3 activities, we will pursue the following aims in the UH3 phase: UH3?1. Complete PWID recruitment, conduct 6- and 12-month follow-up interviews to assess changes in substance use; sexual and injection risk behaviors; HCV and HIV testing; movement through the HCV and HIV care cascade; and utilization of new and expanded services, including SSPs and bridge counselors. UH3?2. Deploy electronic medical record-driven screening for HCV, HIV, and substance use; telehealth support for HCV and HIV treatment; and booster training to optimize services in our pilot clinic(s). Using this as a template, we will recruit, train, and optimize 2?3 additional local clinics to expand regional care access. UH3?3. Using follow-up LHD and HCP surveys in Year 5, epidemiological surveillance, and data on PWID linked to services by bridge counselors and providers trained, we will assess the impact on each care cascade and disseminate findings to local and state partners.